Microglia-derived extracellular vesicles (EVs) contribute to age-related neurodegeneration by promoting neuroinflammation through the release of double-stranded DNA (dsDNA). This study demonstrates that persistent DNA damage in microglia leads to the accumulation of cytosolic DNA fragments, which are sensed as viral-like signals, triggering a type I interferon (IFN) response. In *Erf1*^C/−^ mice, which have a defective XPF-ERCC1 DNA repair pathway, microglia accumulate dsDNA and chromatin fragments in the cytosol, leading to the release of EVs containing dsDNA. These EVs are taken up by IFN-responsive neurons, where they trigger apoptosis and neurodegeneration. The study also shows that delivering recombinant DNase I via EVs to *Erf1*^C/−^ mice effectively reduces cytosolic dsDNA, mitigates neuroinflammation, and delays the onset of neurodegenerative symptoms. The findings reveal a causal mechanism linking DNA damage to neuroinflammation and suggest that targeting EVs to deliver DNase I could be a therapeutic strategy for age-related neurodegenerative diseases. Microglia-derived EVs carry dsDNA and are taken up by neurons, leading to neuronal cell death. The study highlights the role of microglia in neuroinflammation and provides a potential treatment approach for age-related neurodegeneration.Microglia-derived extracellular vesicles (EVs) contribute to age-related neurodegeneration by promoting neuroinflammation through the release of double-stranded DNA (dsDNA). This study demonstrates that persistent DNA damage in microglia leads to the accumulation of cytosolic DNA fragments, which are sensed as viral-like signals, triggering a type I interferon (IFN) response. In *Erf1*^C/−^ mice, which have a defective XPF-ERCC1 DNA repair pathway, microglia accumulate dsDNA and chromatin fragments in the cytosol, leading to the release of EVs containing dsDNA. These EVs are taken up by IFN-responsive neurons, where they trigger apoptosis and neurodegeneration. The study also shows that delivering recombinant DNase I via EVs to *Erf1*^C/−^ mice effectively reduces cytosolic dsDNA, mitigates neuroinflammation, and delays the onset of neurodegenerative symptoms. The findings reveal a causal mechanism linking DNA damage to neuroinflammation and suggest that targeting EVs to deliver DNase I could be a therapeutic strategy for age-related neurodegenerative diseases. Microglia-derived EVs carry dsDNA and are taken up by neurons, leading to neuronal cell death. The study highlights the role of microglia in neuroinflammation and provides a potential treatment approach for age-related neurodegeneration.